Implantable medical device having enhanced endothelial migration features and methods of making the same

ABSTRACT

An implantable medical device having enhanced endothelial migration features, generally comprises: a structural member including a leading edge and a trailing edge interconnected by a third surface region, the leading edge including a second surface region in a generally curvilinear cross-section, and the trailing edge including a fourth surface region in a generally curvilinear cross-section, whereby blood flow over the second surface region generate shear stress at the second surface region without an eddy region in the second surface region.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/103,576, which was filed on May 9, 2011, and is hereby incorporatedin its entirety.

BACKGROUND OF THE INVENTION

The present invention relates generally to implantable medical devicesand more particularly to controlling surface properties of implantablebiocompatible materials suitable for fabrication of implantable medicaldevices.

Implantable medical devices are fabricated of materials that aresub-optimal in terms of the biological response they elicit in vivo.Many conventional materials used to fabricate implantable devices, suchas titanium, polytetrafluoroethylene, silicone, carbon fiber andpolyester, are used because of their strength and physiologically inertcharacteristics. However, tissue integration onto these materials istypically slow and inadequate. Certain materials, such as silicone andpolyester, elicit a significant inflammatory, foreign body response thatdrives fibrous encapsulation of the synthetic material. The fibrousencapsulation may have significant adverse effects on the implant.Moreover, conventional biomaterials have proved inadequate in elicitinga sufficient healing response necessary for complete device integrationinto the body. For example, in devices that contact blood, such asstents and vascular grafts, attempts to modify such devices to promoteendothelial cell adhesion may have a concomitant effect of making thedevices more thrombogenic.

When implanted, conventional blood-contacting implantable devices, suchas stents, stent-grafts, grafts, valves, shunts and patches, fail todevelop a complete endothelial layer, thereby exposing the devicematerial to thrombus formation or smooth muscle cell proliferation, andultimate failure of the implanted device. It has been recognized that,when implanted into the body, metals are generally considered to havesuperior biocompatibility than polymers used to fabricate commerciallyavailable polymeric grafts.

In investigating cellular interactions with prosthetic materialsurfaces, it has been found that cell adhesion to the material surfaceis mediated by integrins present on cell membranes that interact withthe prosthetic surface. Integrins are the most prominent member of aclass of extracellular matrix (ECM) adhesion receptors. Integrins are alarge family of heterodimeric transmembrane proteins with different αand β subunits. Integrins are regulated at several levels. Modulation ofthe affinity of the adhesion receptor for ligand, termed affinitymodulation, is a mechanism for activation of platelet aggregation and isbelieved to underlie activation of leukocyte adhesion. Adhesivestrengthening by clustering of adhesion receptors or bycytoskeletal-dependent processes such as cell spreading has been shownto be crucial for strong cellular attachment, control of cell growth andcell motility. Under high shear forces present in flowing blood,leukocytes first tether, then roll along the vessel surface. When alocal signal, e.g., a cytokine, is released in their vicinity, theleukocyte arrests, develops a firm adhesion then migrates across theendothelium. Tethering, rolling, arrest and adhesion tightening are allknown to result from activation of leukocyte integrins.

Once adhered to a surface, cell spreading and migration are associatedwith assembly of focal adhesion junctions. Cell migration entails thecoordination of cytoskeletal-mediated process extension, i.e., filopodiaand lamellopodia, formation of adhesive contacts at the leading edge ofa cell, breaking adhesive contacts, and cytoskeletal retraction at thetrailing edge of the cell. Focal adhesions are comprised of integrins asthe major adhesion receptors along with associated cytoplasmic plaqueproteins. Assembly of focal adhesions is regulated by extracellularligand binding events and by intracellular signaling events. Ligandbinding controls localization of β1- and β3-containing integrins intofocal adhesions. The cytoplasmic domains of the β subunits haveintrinsic signals for focal adhesion localization, but incorporation ofthe integrins into focal adhesions is prevented by the α subunits of theheterodimers. Ligand binding, however, relieves this inhibition andallows the subunit cytoplasmic tail signals to recruit the integrindimmer into the focal adhesion.

Attempts at coating implanted metal devices, such as stents, withproteins that contain the Arg-Gly-Asp (RGD) attachment site have beenmade with some success. The RGD sequence is the cell attachment site ofa large number of adhesive extracellular matrix, blood, and cell surfaceproteins and many of the known integrins recognize the RGD sequence intheir adhesion protein ligands. Integrin-binding activity may also bereproduced by synthetic peptides containing the RGD sequence. However,bare metal implanted materials will not, of course, have native RGDattachment sites. Thus, metal implantable devices, such as stents, havebeen derivitized with polymers having RGD attachment sites bound to thepolymer matrix.

It has been found that when prosthetic materials are implanted, integrinreceptors on cell surfaces interact with the prosthetic surface. Whencells come into contact with the extracellular matrix, such as aprosthetic surface, their usual response is to extend filopodia, andintegrins at the tip of the filopodia bind to the extracellular matrixand initiate the formation of focal adhesions. Actin-rich lamellipodiaare generated, often between filopodia, as the cell spreads on theextracellular matrix. Fully developed focal adhesions and associatedactin stress fibers ensue. These same evens occur during cell migrationas cells extend lamellipodia and form focal adhesions to derive thetraction necessary for movement. Giancotti, F. G., et al. Science,285:13 August 1999, 1028-1032.

The integrin receptors are specific for certain ligands in vivo. If aspecific protein is adsorbed on a prosthetic surface and the ligandexposed, cellular binding to the prosthetic surface may occur byintegrin-ligand docking. It has also been observed that proteins bind tometals in a more permanent fashion than they do to polymers, therebyproviding a more stable adhesive surface. The conformation of proteinscoupled to surfaces of most medical metals and alloys appears to exposegreater numbers of ligands and attract endothelial cells having surfaceintegrin clusters to the metal or alloy surface, preferentially overleukocytes.

Because of their greater adhesive surface profiles, metals are alsosusceptible to short-term platelet activity and/or thrombogenicity.These deleterious properties may be offset by administration ofpharmacologically active antithrombogenic agents in routine use today.Surface thrombogenicity usually disappears 1-3 weeks after initialexposure. Antithrombotic coverage is routinely provided during thisperiod of time for coronary stenting. In non-vascular applications suchas musculoskeletal and dental, metals have also greater tissuecompatibility than polymers because of similar molecular considerations.The best article to demonstrate the fact that all polymers are inferiorto metals is van der Giessen, W J. et al. Marked inflammatory sequelaeto implantation of biodegradable and non-biodegradable polymers inporcine coronary arteries, Circulation, 1996:94(7):690-7.

Normally, endothelial cells (EC) migrate and proliferate to coverdenuded areas until confluence is achieved. Migration, quantitativelymore important than proliferation, is affected by exposure of the EC toblood flow. Under static conditions or in the presence of minor shearstress, for example, about 1.5 dynes/cm², EC have been observed tomigrate at speeds between about 10 μm/hr to about 15 μm/hr. Palmaz, J.C., Bailey, S., Marton, D., and Sprague, E. Influence of stent designand material composition on procedure outcome J. Vasc. Surg. 2002;36:1031-1039. Also, the cause of restenosis includes vessel injury dueto pressure from stent expansion and neointimal thickening due todecrease in vessel wall shear stress (WSS).

EC migrate by a rolling motion of the cell membrane, coordinated by acomplex system of intracellular filaments attached to clusters of cellmembrane integrin receptors, specifically focal contact points. Theintegrins within the focal contact sites are expressed according tocomplex signaling mechanisms and eventually couple to specific aminoacid sequences in substrate adhesion molecules. An EC has roughly 16-22%of its cell surface represented by integrin clusters. Davies, P. F.,Robotewskyi A., Griem M. L. Endothelial cell adhesion in real time. J.Clin. Invest. 1993; 91:2640-2652, Davies, P. F., Robotewski, A., Griem,M. L., Qualitiative studies of endothelial cell adhesion, J. Clin.Invest. 1994; 93:2031-2038. This is a dynamic process, which involvesmore than 50% remodeling in 30 minutes.

The focal adhesion contacts vary in size and distribution, but 80% ofthem measure less than 6 μm², with the majority of them being about 1μm², and tend to elongate in the direction of flow and concentrate atleading edges of the cell. Although the process of recognition andsignaling to determine specific attachment receptor response toattachment sites is not completely understood, availability ofattachment sites will favorably influence attachment and migration. Itis known that materials commonly used as medical grafts, such aspolymers, do not become covered with EC and therefore do not heal afterthey are placed in the arteries. Furthermore, heterogeneities ofmaterials in contact with blood flow are preferably controlled by usingvacuum deposited materials.

There have been numerous attempts to increase endothelialization ofimplanted medical devices such as stents, including covering the stentwith a polymeric material (U.S. Pat. No. 5,897,911), imparting adiamond-like carbon coating onto the stent (U.S. Pat. No. 5,725,573),covalently binding hydrophobic moieties to a heparin molecule (U.S. Pat.No. 5,955,588), coating a stent with a layer of blue to black zirconiumoxide or zirconium nitride (U.S. Pat. No. 5,649,951), coating a stentwith a layer of turbostratic carbon (U.S. Pat. No. 5,387,247), coatingthe tissue-contacting surface of a stent with a thin layer of a Group VBmetal (U.S. Pat. No. 5,607,463), imparting a porous coating of titaniumor of a titanium alloy, such as Ti—Nb—Zr alloy, onto the surface of astent (U.S. Pat. No. 5,690,670), coating the stent, under ultrasonicconditions, with a synthetic or biological, active or inactive agent,such as heparin, endothelium derived growth factor, vascular growthfactors, silicone, polyurethane, or polytetrafluoroethylene (U.S. Pat.No. 5,891,507), coating a stent with a silane compound with vinylfunctionality, then forming a graft polymer by polymerization with thevinyl groups of the silane compound (U.S. Pat. No. 5,782,908), graftingmonomers, oligomers or polymers onto the surface of a stent usinginfrared radiation, microwave radiation or high voltage polymerizationto impart the property of the monomer, oligomer or polymer to the stent(U.S. Pat. No. 5,932,299). However, all these approaches do not addressthe lack of endothelialization of polymer grafts.

Overall rate to reach confluence for the endothelial cells on the bloodcontact surface of implanted medical device is mainly determined by twofactors, the rate of cell movement and rate of cell proliferation, withthe first being more important. The rate of cell movement furthercomprises three interrelated steps. Initially, a cell forms lamellipodiaand filopodia that protrude outward. This step involves reassembly ofactins in the forefront of lambaepolia. After protrusion of lamellipodiafrom one or multiple points from the cell membrane, the front end of thelamellipodia will form a close attachment, called focal adhesion point,to the substratum through the interaction of integrin on the cellmembrane and extracellular matrix binding site. The final step of cellmovement involves the contraction of the posterior end through theaction of myosin II. The formation of a focal adhesion point is criticalfor the cell movement because the protruding lamellipodia will otherwisefold back. Without the tension force from the focal adhesion point, acell loses the contraction from the posterior end and hence stopsmoving.

Availability of attachment sites on the substratum is not only importantfor the focal adhesion point formation, but also important forpropagation. It has been shown that when cells are forced to spread,they survive better and proliferate faster than cells that are confinedto the same amount of surface area (Science 276:1425-1428, 1997). Thismay explain why spreading of neighbor cells stimulate a cell toproliferate, after cells are lost from epithelium.

The formation of extracellular matrix (ECM) is, to much extent,determined by the cells within it because molecules which form ECM aresecreted by the cells. Subsequently, the structure of the ECM, and hencethe distribution of attachment sites on the ECM for the integrinbinding, determines the focal adhesion point formation, the criticalstep in cell movement. Therefore, proper distribution of integrinbinding sites on the surface of an implanted medical devicesubstantially determines the speed of reendothelialization from the endssurrounding the device.

There still remains a need for a medical device that stimulatesendothelial proliferation and movement when implanted in order to forman endothelial layer over the medical device. Furthermore, there is aremaining need for a method of fabricating such a medical device.

SUMMARY OF THE INVENTION

In one embodiment, an implantable medical device having enhancedendothelial migration features, comprises: a structural member includinga leading edge and a trailing edge interconnected by a third surfaceregion, the leading edge including a second surface region in agenerally curvilinear cross-section, and the trailing edge including afourth surface region in a generally curvilinear cross-section, wherebyblood flow over the second surface region generate shear stress at thesecond surface region without an eddy region in the second surfaceregion.

In another embodiment, the implantable biocompatible material includes aplurality of geometrically functional features. In one embodiment, theimplantable biocompatible material includes a plurality of groovesdisposed on at least one of the trailing edge, leading edge, and surfaceregions of the structural member.

In a further embodiment, a method of forming an implantable medicaldevice having enhanced endothelial migration features, comprises:forming a structural member including a leading edge and a trailing edgeinterconnected by a third surface region, the leading edge including asecond surface region in a generally curvilinear cross-section, and thetrailing edge including a fourth surface region in a generallycurvilinear cross-section, whereby blood flow over the second surfaceregion generate shear stress at the second surface region without aneddy region in the second surface region.

The foregoing and other features and advantages of the disclosure areapparent from the following detailed description of exemplaryembodiments, read in conjunction with the accompanying drawings; whereinlike structural or functional elements are designated by like referencenumerals.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a perspective view of an embodiment including evenlydistributed elevated geometric physiologically functional features onthe surface of an implantable material.

FIG. 2 is cross-sectional view of FIG. 1 along line 2-2.

FIG. 3 is a perspective view of an embodiment including evenlydistributed chemically defined geometric physiologically functionalfeatures on the surface of an implantable material.

FIG. 4 is a cross-sectional view of FIG. 3 along line 4-4.

FIGS. 5A-5D are cross-sectional diagrammatic views of an embodiment, thecombination of a-d representing the steps to make an inventiveimplantable material with elevated geometric physiologically functionalfeatures.

FIGS. 6A-6D are cross-sectional diagrammatic views of an embodiment, thecombination of a-d representing the steps to make an inventiveimplantable material with chemically defined geometric physiologicallyfunctional features.

FIGS. 7A-7B are cross-sectional diagrammatic views of one embodiment;FIG. 7C is a top view of one embodiment; and FIGS. 7D-7E arecross-sectional diagrammatic views of one embodiment of making theimplantable material.

FIGS. 8A-8D are cross-sectional diagrammatic views of one embodiment.

FIGS. 9A-9B are cross-sectional diagrammatic views of one embodiment.

FIG. 10 is a cross-sectional view of an artery having an arterial wallincluding an implantable medical device.

FIG. 11 is an enlarged cross-sectional view from circle 11 in FIG. 10 ofthe implantable medical device, in accordance with one embodiment.

FIG. 12A is a cross-sectional view of one embodiment of the structuralmember having a generally rounded rectangular cross-section; FIG. 12B isa cross-sectional view of one embodiment of the structural member havinga generally hexagonal cross-section; and FIGS. 12C-12D arecross-sectional views of one embodiment of the structural memberentirely lacking an eddy region.

FIG. 13A is a cross-sectional view of one embodiment of the trailingedge of a structural member having a generally rounded rectangularcross-section; and FIGS. 13B-13C are cross-sectional views of oneembodiment of the trailing edge of the structural member 206 having amodified cross-section.

FIG. 14A is a perspective view of one embodiment of the structuralmember including a luminal surface, a leading edge, and a trailing edge;FIG. 14B is a perspective view of one embodiment of the structuralmember including a luminal surface, the leading edge, and the trailingedge including grooves disposed therein or thereon.

FIG. 15 is a perspective view of one embodiment of the structural memberincluding a main highway of the grooves.

FIGS. 16A-16B are photographs of human aortic EC migration onto 1×1-cm,316L stainless steel flat coupons after fixation and Giemsa staining,where entire sheet then was placed into parallel plate flow chamber andexposed to fluid-imposed arterial level shear (15 dynes/cm²), as shownin FIG. 16A, and low shear (1.5 dynes/cm²), as shown in FIG. 16B, wallstress on right for 4 days, and the arrow indicates that direction offlow.

FIG. 17 is a graph showing the percentage of total area of surfaceobstacles covered by ECs after 4 days with flow at 15 dynes/cm²; whereECs were grown to confluence on polyester film sheet with attachedpieces of polyester film of increasing thickness serving as obstacles;and Asterisks indicate statistically significant difference comparedwith 25 μm.

FIG. 18 is a photograph of human aortic ECs migrating on stainless steelin direction of arrow stained with Giemsa and 200× magnification;confluent human aortic ECs were allowed to migrate from firm collagengel onto implanted 1×1-cm flat stainless steel coupons with staticculture conditions for 7 days; on encounter with surface scratch, cellsdeviate to follow feature; and three cells in middle of field arealigned on single scratch.

FIG. 19 is a photograph of human aortic ECs migrating on uniformlyscratched stainless steel surface and stained with Giemsa stain at 200×magnification; cells migrated from confluent human aortic EC covered gelonto flat stainless steel coupons as described previously; and parallelscratch pattern was created with 320-grain carbide sand paper.

FIG. 20 is a graph showing Bars which indicate mean number of ECs permm² on stainless steel microfabricated surfaces, with square sectiongrooves from 7 to 20 μm wide; grooves of defined width were created withphotolithographic process; grooved stainless steel 1×1-cm coupons wereimplanted on endothelialized gel surface as described below, and cellswere allowed to migrate onto surface for 7 days with static cultureconditions; control indicates flat surface; and surface with 15-μmgrooves has significantly larger cell population.

FIG. 21A is a cross-sectional view of an artery having an arterial wallincluding an implantable medical device.

FIG. 21B is an enlarged perspective transverse cross-sectional view fromcircle 21B in FIG. 21A of the implantable medical device, in accordancewith one embodiment.

FIG. 22A is a cross-sectional view of an artery having an arterial wallincluding an implantable medical device.

FIG. 22B is an enlarged perspective transverse cross-sectional view fromcircle 22B in FIG. 22A of the implantable medical device, in accordancewith one embodiment.

The foregoing and other features and advantages of the disclosure areapparent from the following detailed description of exemplaryembodiments, read in conjunction with the accompanying drawings; whereinlike structural or functional elements are designated by like referencenumerals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the embodiments disclosed herein, the capacity forcomplete endothelialization of conventional implantable materials,including metals and polymers, may be enhanced by imparting a pattern ofchemically and/or physiochemically active geometric physiologicallyfunctional features onto a blood contacting surface of the implantablematerial. The inventive implantable devices may be fabricated ofpolymers, pre-existing conventional wrought metallic materials, such asstainless steel or nitinol hypotubes, or may be fabricated by thin filmvacuum deposition techniques. In accordance with one embodiment, theinventive implantable materials may be vacuum deposited and resultingdevices by vacuum deposition of either or both of the base implantmaterial and the chemically and/or physiochemically active geometricphysiologically functional features. Vacuum deposition permits greatercontrol over many material characteristics and properties of theresulting material and formed device. For example, vacuum depositionpermits control over grain size, grain phase, grain materialcomposition, bulk material composition, surface topography, mechanicalproperties, such as transition temperatures in the case of a shapememory alloy. Moreover, vacuum deposition processes will permit creationof devices with greater material purity without the introduction oflarge quantities of contaminants that adversely affect the material and,therefore, the mechanical and/or biological properties of the implanteddevice. Vacuum deposition techniques also lend themselves to fabricationof more complex devices than those that are manufactured by conventionalcold-working techniques. For example, multi-layer structures, complexgeometrical configurations, extremely fine control over materialtolerances, such as thickness or surface uniformity, are all advantagesof vacuum deposition processing.

In vacuum deposition technologies, materials are formed directly in thedesired geometry, e.g., planar, tubular, etc. The common principle ofvacuum deposition processes is to take a material in a minimallyprocessed form, such as pellets or thick foils, known as the sourcematerial and atomize them. Atomization may be carried out using heat, asis the case in physical vapor deposition, or using the effect ofcollisional processes, as in the case of sputter deposition, forexample. In some forms of deposition a process such as laser ablation,which creates microparticles that typically consist of one or moreatoms, may replace atomization; the number of atoms per particle may bein the thousands or more. The atoms or particles of the source materialare then deposited on a substrate or mandrel to directly form thedesired object. In other deposition methodologies, chemical reactionsbetween ambient gas introduced into the vacuum chamber, i.e., the gassource, and the deposited atoms and/or particles are part of thedeposition process. The deposited material includes compound speciesthat are formed due to the reaction of the solid source and the gassource, such as in the case of chemical vapor deposition. In most cases,the deposited material is then either partially or completely removedfrom the substrate, to form the desired product.

A first advantage of vacuum deposition processing is that vacuumdeposition of the metallic and/or pseudometallic films permits tightprocess control and films may be deposited that have a regular,homogeneous atomic and molecular pattern of distribution along theirfluid-contacting surfaces. This avoids the marked variations in surfacecomposition, creating predictable oxidation and organic adsorptionpatterns and has predictable interactions with water, electrolytes,proteins and cells. In particular, EC migration is supported by ahomogeneous distribution of binding domains that serve as natural orimplanted cell attachment sites in order to promote unimpeded migrationand attachment.

Secondly, in addition to materials and devices that are made of a singlemetal or metal alloy layer, the inventive grafts may be comprised of alayer of biocompatible material or of a plurality of layers ofbiocompatible materials formed upon one another into a self-supportingmultilayer structure because multilayer structures are generally knownto increase the mechanical strength of sheet materials, or to providespecial qualities by including layers that have special properties suchas superelasticity, shape memory, radio-opacity, corrosion resistance,etc. A special advantage of vacuum deposition technologies is that it ispossible to deposit layered materials and thus films possessingexceptional qualities may be produced (cf., H. Holleck, V. Schier:Multilayer PVD coatings for wear protection, Surface and CoatingsTechnology, Vol. 76-77 (1995) pp. 328-336). Layered materials, such assuperstructures or multilayers, are commonly deposited to take advantageof some chemical, electronic, or optical property of the material as acoating; a common example is an antireflective coating on an opticallens. Multilayers are also used in the field of thin film fabrication toincrease the mechanical properties of the thin film, specificallyhardness and toughness.

Thirdly, the design possibilities for possible configurations andapplications of the inventive graft are greatly realized by employingvacuum deposition technologies. Specifically, vacuum deposition is anadditive technique that lends itself toward fabrication of substantiallyuniformly thin materials with potentially complex three dimensionalgeometries and structures that cannot be cost-effectively achieved, orin some cases achieved at all, by employing conventional wroughtfabrication techniques. Conventional wrought metal fabricationtechniques may entail smelting, hot working, cold working, heattreatment, high temperature annealing, precipitation annealing,grinding, ablation, wet etching, dry etching, cutting and welding. Allof these processing steps have disadvantages including contamination,material property degradation, ultimate achievable configurations,dimensions and tolerances, biocompatibility and cost. For exampleconventional wrought processes are not suitable for fabricating tubeshaving diameters greater than about 20 mm, nor are such processessuitable for fabricating materials having wall thicknesses down to about1 μm with sub-μm tolerances.

The embodiments disclosed herein takes advantage of the discoveredrelationship between chemically or physiochemically-active geometricphysiologically functional features defined and distributed on a bloodcontact surface and enhanced endothelial cell binding, proliferation andmigration over the blood contact surface of the implantable material.The embodiments disclosed herein involves focal adhesion point formationduring cellular movement and the well-established observation known asanchorage dependence, that spreading cells proliferate faster thannon-spreading cells. The addition of a patterned array of geometricphysiologically functional features having a hydrophobic, hydrophilic orsurface energy difference relative to the surface onto which thegeometric physiologically functional features are added, enhances thebinding, proliferation and migration of endothelial cells to and betweenthe geometric physiologically functional features and across thesurface.

The geometric physiologically functional features disclosed herein maybe formed on, in, or through one or more layers of vacuum depositedbiocompatible material. In a first embodiment, the one or more layers ofvacuum deposited biocompatible material are deposited on a layer of bulkmaterial. In a second embodiment, a plurality of layers of vacuumdeposited biocompatible material is deposited on one another to form aself-supporting multilayer structure. Each of the first and secondembodiments includes several aspects. In a first aspect, the geometricphysiologically functional features may have a non-zero thicknesscorresponding to a thickness of one or more layers of the vacuumdeposited material. Alternatively, in other aspects, the geometricphysiologically functional features may have a zero thickness or athickness greater than one or more layers of the vacuum depositedmaterial.

Below about 3 μm in thickness, the interactions between endothelialcells and the geometric physiologically functional features areprimarily chemical and electrochemical. Geometric physiologicallyfunctional features having thicknesses greater than 3 μm and up to about20 μm may also be employed, it being understood that as the thickness ofthe geometric physiologically functional feature increases there is adecreasing chemical and/or electrochemical interaction between thegeometric physiologically functional feature and the endothelial cellsand an increasing physical interaction (topographic guidance effect).

Additionally, it has been found that by employing UV irradiation tooxidized titanium or titanium-alloy surfaces, photochemical alterationof the surface titanium oxides alter the hydrophobicity of the exposedtitanium oxides and act as affinity binding and migration sites forendothelial cell attachment and proliferation across a titanium ortitanium-alloy surface. Where UV irradiation is employed, the thicknessof the photochemically altered regions of titanium oxide are, for allpractical purposes, 0 μm. Thus, within the context of the presentapplication, the term “geometric physiologically functional features” isintended to include both physical members and photochemically-alteredregions having thicknesses down to 0 μm.

In FIG. 1, a portion of an implantable material 10 showing the surface12 with described elevated geometric physiologically functional features14 is illustrated. The geometric physiologically functional features areelevated from the surface of the implantable material to a heightranging from about 1 nm to about 20 μm. Preferably, the height of thegeometric physiologically functional feature 14 ranges from about 1 nmto about 3 μm. The shape of geometric physiologically functionalfeatures can be either circular, square, rectangle, triangle, parallellines, straight or curvilinear lines or any combination thereof. Each ofthe geometric physiologically functional features is preferably fromabout 1 nm to about 75 μm, and preferably from about 1 nm to 50 μm infeature width 16, or feature diameter if the geometric physiologicallyfunctional feature is circular. A gap distance 18 between each of thegeometric physiologically functional features may be less than, aboutequal to or greater than the feature width 16, i.e., between about 1 nmto about 75 μm edge-to-edge.

FIG. 2 is a cross-sectional view along line 2-2 in FIG. 1. One of theelevated geometric physiologically functional features 14 is shown onthe surface 12 of the implantable material.

In FIG. 3, a layer of a titanium or titanium-alloy material 20 isheating to oxidize and form titanium dioxide on the surface of thematerial 20. In one embodiment, the layer of titanium or titanium-alloymaterial 20 is deposited over one or more layers of vacuum depositedmaterial in a self-supporting multilayer structure. In anotherembodiment, the layer of titanium or titanium-alloy material 20 isdeposited over a bulk material that may have one or more layers ofvacuum deposited material deposited thereon.

The geometric physiologically functional features 24 are formed byexposing the layer of material 20 to UV through a pattern mask. UVirradiation alters the titanium oxides in the areas of geometricphysiologically functional features 24, thereby chemically altering thegeometric physiologically functional features 24 relative to thesurrounding surface area 22 of layer of material 20. The shape ofgeometric physiologically functional features can be circular, square,rectangle, triangle, parallel lines, intersecting lines or anycombination. Each of the geometric physiologically functional featuresis from about 1 nanometer to about 75 μm, and preferably from about 1nanometer to about 50 μm in feature width 26, or feature diameter if thegeometric physiologically functional feature is circular. The gapdistance 28 between each component of the geometric physiologicallyfunctional features may be less than, about equal to or greater than thefeature width 26.

FIG. 4 is a cross-sectional view of FIG. 3 along line 4-4. The describedgeometric physiologically functional features 24 are indicated by thedotted lines, which indicate that the geometric physiologicallyfunctional features 24 are at the same level of the surrounding surface22.

Referring to FIG. 5A, a portion of an implantable material 46 withsurface 42 and 44 is shown.

Referring to FIG. 5B, a machined mask 48 having laser-cut holes 40 ofdefined size ranging from about 1 nm to about 75 μm, and preferably fromabout 1 nm to 50 μm, patterned throughout coats at least one surface 42of the implantable material 46 and is tightly adhered to the coveredsurface 42.

Referring to FIG. 5C, a thin film of material 30 was deposited into thespace as defined by the holes 40, as seen in FIG. 5B, in the mask 48 bythin film deposition procedures.

Referring to FIG. 5D, after deposition, the mask is removed to revealthe geometric physiologically functional features 49 patterned acrossthe at least one surface 42 of the implantable material 46.

As described above, the shape of the holes in the mask could be in anyof the shapes described for the geometric physiologically functionalfeatures including: circle, square, rectangle, triangle, parallel linesand intersecting lines, or any combination thereof. In the thin filmdeposition embodiment of the manufacturing the geometric physiologicallyfunctional features, the geometric physiologically functional featuresare elevated from the surface of the implantable material. The thicknessof the geometric physiologically functional features is based upon thethickness of the holes in the mask, the thickness ranging from about 1nm to about 20 micrometers. Preferably, the thickness of the holes inthe mask range from about 1 nm to about 3 micrometers.

The variations of geometric physiologically functional features may beadded to a surface of an implantable biocompatible material by vacuumdepositing a layer or layers of biocompatible material on the surface.In one embodiment, the geometry of the layer or layers of depositedmaterial defines the geometric physiologically functional features. Forexample, an implantable material 100 has a surface 104, as illustratedin FIG. 7A. In one embodiment, the implantable biocompatible materialmay comprise one or more layers 102 of vacuum deposited material formedinto a self-supporting structure, as illustrated by FIG. 7A showing afirst layer 102 a, a second layer 102 b, a third layer 102 c, a fourthlayer 102 d, and a fifth layer 102 e. In another embodiment, theimplantable biocompatible material includes a bulk material, either abulk material alone or a bulk material covered by the one or more layers102 a-102 e of vacuum deposited biocompatible material. Five layers 102a-102 e of vacuum deposited material are illustrated; however, anynumber of layers may be included as desired or appropriate.

The one or more layers 102, may have thicknesses that are the same ordifferent as desired or appropriate. Each layer may have a thickness ina range from about 1 nanometer to about 20 micrometers, from about 1nanometer to about 10 micrometers, from about 1 nanometer to about 5micrometers, or from about 1 nanometer to about 3 micrometers.Alternating layers 102 of varying thicknesses may be applied as toaccommodate the geometric physiologically functional features.

In this embodiment, the geometric physiologically functional featuresmay be added to the surface 104 by adding one or more layers 102 ofvacuum deposited material. For example, referring to FIGS. 7B-7E, in oneprocess, a mask 106 having holes 108 of defined size disposedtherethrough and patterned throughout coats and is tightly adhered to atleast a first portion of the surface 104. The holes 108 may be cutthrough the mask 106, for example, by using a laser or other method forforming holes through a material as known in the art, or the mask 106may be fabricated including the holes 108 as may be known in the art.The thickness of the holes 108 may range about 1 nanometer to about 20micrometers, from about 1 nanometer to about 10 micrometers, from about1 nanometer to about 5 micrometers, or from about 1 nanometer to about 3micrometers.

The shape of the holes 108 as seen in FIG. 7C or as looking in thedirection of arrow 110 in FIG. 7B may be any of the shapes described forthe geometric physiologically functional features including: circle,square, rectangle, triangle, polygonal, hexagonal, octagonal,elliptical, parallel lines and intersecting lines, or any combinationthereof. The holes 108 may have a width 112, or diameter 112 if theholes are circular, in a range between about 1 nanometer and about 75micrometers, between about 1 nanometer and about 50 micrometers, betweenabout 1 nanometer and about 2000 nanometers, or between about 1nanometer and about 200 nanometers. Adjacent holes 108 may be spacedapart by a distance D in a range from about 1 nanometer to about 20micrometers, from about 1 nanometer to about 10 micrometers, from about1 nanometer to about 5 micrometers, or from about 1 nanometer to about 3micrometers. The distance D may be less than, about equal to or greaterthan the width 112. In another embodiment (not shown), the width 112 ofeach of the holes 108 and/or the distance D between adjacent holes 108may vary in size to form a patterned array of the holes 108.

Referring to FIG. 7D, a layer 114 of material was deposited into a spaceas defined by the holes 108 in the mask 106 by vacuum deposition. Thelayer 114 has a thickness essentially the same as that of the mask 106.In some embodiments, the thickness of the mask may be variable acrossthe mask 106. After removal of the mask 106, as shown in FIG. 7E,geometric physiologically functional features 116 are revealed patternedacross the surface 104 of the implantable material 100. Each of thegeometric physiologically functional features 116 includes a top surface118. Each of the geometric physiologically functional features 116 hasdimensions as described hereinabove for the holes 108 in the mask 106.

In another embodiment where geometry of the layer or layers of depositedmaterial defines the geometric physiologically functional features, apatterned array of recesses may be formed each having a hydrophobic,hydrophilic or surface energy difference relative to the surface intowhich the recesses are added, meaning a top most surface of thedeposited layers, the difference enhancing the binding, proliferationand migration of endothelial cells to and between the recesses andacross the surfaces, recessed and top most. The hydrophobic, hydrophilicor surface energy differences relative to the surface may be formed, byway of example, any of the methods disclosed in commonly assigned U.S.patent application Ser. No. 12/428,981, filed Apr. 23, 2009,incorporated by reference herein.

In this embodiment, the recesses may be formed by a relative lack ofdeposition of a layer or layers onto a surface, or by machining recessesthrough a layer or layers of material vacuum deposited on a surface. Forexample, to produce a pattern of recesses similar to the pattern ofgeometric physiologically functional features 116 illustrated in FIG.7E, in one example, a process begins by executing the steps describedhereinabove with regard to FIGS. 7A-7E, to produce the pattern ofgeometric physiologically functional features 116 illustrated in FIG.7E, except in this embodiment, the layer 114 of material is asacrificial layer of material that is removed in a subsequent step.

Referring to FIGS. 8A and 8B, a layer 120 of material is deposited intospaces between the geometric physiologically functional features 116 byvacuum deposition. The layer 120 has a thickness essentially the same asthat of the geometric physiologically functional features 116. In thisembodiment, after vacuum deposition of the layer 120, the geometricphysiologically functional features 116 of the sacrificial layer 114 areremoved, for example, by chemical etching or other method known in theart to reveal geometric physiologically functional features 122patterned across the surface 104 of the implantable material 100. Eachof the geometric physiologically functional features 122 is a recessthat has a thickness or depth between a surface 124 of the layer 120 andthe surface 104.

The shape of the recesses 122 as seen looking in the direction of arrow126 in FIG. 8B may be any of the shapes described for the geometricphysiologically functional features including: circle, square,rectangle, triangle, polygonal, hexagonal, octagonal, elliptical,parallel lines and intersecting lines, or any combination thereof. Therecesses 122 may have the width 112, or diameter if the recesses 122 arecircular, in a range between about 1 nanometer and about 75 micrometers,alternatively between about 1 nanometer and about 50 micrometers,alternatively between about 1 nanometer and about 2000 nanometers, oralternatively between about 1 nanometer and about 200 nanometers.Adjacent recesses 122 may be spaced apart by the distance D in a rangefrom about 1 nanometer to about 20 micrometers, from about 1 nanometerto about 10 micrometers, from about 1 nanometer to about 5 micrometers,or from about 1 nanometer to about 3 micrometers. The distance D may beless than, about equal to or greater than the width 112. In anotherembodiment (not shown), the width 112 of each of the recesses 122 and/orthe distance D between adjacent recesses 122 may vary in size to form apatterned array of the recesses 122.

In another embodiment, the recesses 122 having width and spacing asdescribed hereinabove with regard to FIGS. 8A and 8B may be formed bymachining the recesses 122 through a layer or layers 127 of vacuumdeposited material. For example, an implantable material 130 having asurface 132, may comprise a bulk material 134, and the one or morelayers 127 of vacuum deposited material, as illustrated in FIG. 9A.

Alternatively, as shown in FIG. 8C, the geometric physiologicallyfunctional features 116 themselves include a plurality of depositedlayers, wherein the geometric physiologically functional features 116include the first layer 102 a, the second layer 102 b, and the thirdlayer 102 c. The geometric physiologically functional features 116 aredeposited through a mask as previously indicated, on top of structuralmaterial of the stent or other medical device include deposited layer102 d and 102 e. Alternatively, the geometric physiologically functionalfeatures 116 include the first layer 102 a and the second layer 102 b,deposited through the mask whereby the structural material of the stentor other medical device includes the layers 102 c-102 d. Alternatively,the geometric physiologically functional features 116 include the firstlayer 102 a, the second layer 102 b, the third layer 102 c, and thefourth layer 102 d, whereby the structural material of the stent orother medical device includes the fifth layer 102 e. When additionallayers 102 a-102 d are included in the geometric physiologicallyfunctional feature 116, the thickness of the layers as deposited can bemodified to be a narrower or decreased thickness as to allow for thegeometric physiologically functional feature 116 to be adjusted to aparticular thickness. The layers of different vacuum deposited materialscan be deposited to create the elevated surfaces having inherentlydifferent material properties. Alternatively, layers of the same vacuumdeposited material can be deposited having differences in grain size,grain phase, and/or surface topography or variations of hydrophobic,hydrophilic or surface energy difference relative to the surface of thestent or structural material.

Alternatively, as shown in FIG. 8D, the recesses 122 may include aplurality of layers 102 to provide for differences in grain size, grainphase, and/or surface topography or variations of hydrophobic,hydrophilic or surface energy difference relative to the surface of thestent or structural material. The recesses 122 may be formed by thesurface 124 being deposited through a mask as to form the layer 120 thatgives rise to the plurality of recesses 122 with a wall 123. As such,the recesses 122 include an inner wall 123 including the first layer 102a, the second layer 102 b, and the third layer 102 c, whereby thesurface 104 is on layer 102 d, which is exposed on the bottom of therecess 122 and surface 124 is on top of layer 102 a. Alternatively, therecesses 122 may include a wall of the first layer 102 a and the secondlayer 102 b, whereby the surfaces 124 are deposited through a mask, andthe structural material of the stent or other medical device includesthe layers 102 d-102 e. Alternatively, the recesses 122 include a wallof the first layer 102 a, the second layer 102 b, the third layer 102 c,and the fourth layer 102 d, and surfaces 124 are deposited through amask whereby surface 102 e that acts as the surface 104 of thestructural material of the medical device. When additional layers 102a-102 d are included as the wall in the geometric physiologicallyfunctional feature 116, the thickness of the layers as deposited can bemodified to be a narrower or decreased thickness as to allow for thegeometric physiologically functional feature 116 to be adjusted to aparticular thickness. The layers of different vacuum deposited materialscan be deposited to create recesses having inherently different materialproperties. Alternatively, layers of the same vacuum deposited materialcan be deposited having differences in grain size, grain phase, and/orsurface topography or variations of hydrophobic, hydrophilic or surfaceenergy difference relative to the surface of the stent or structuralmaterial.

Referring to FIG. 9B, recesses 136 may be machined into the surface 132of the implantable material 130 to have a depth greater than a thicknessof a first layer of material 127 a or recesses 138 may be machined intothe surface 132 of the implantable material 130 to have a depth greaterthan a thickness of the first and second layers 127 a, 127 b ofmaterial. Two layers are illustrated for convenience of explanation andillustration; however, any number of layers 127 of material may be usedas desired or appropriate. In this aspect, each of the recesses 136 hasa thickness or depth between the surface 132 of the layer 127 and asurface 140 that is within a second layer 127 b. Similarly, each of therecesses 138 has a thickness or depth between the surface 132 of thelayer 127 a and a surface 142 that is within the bulk material 134.

An implantable material including geometric physiologically functionalfeatures comprising a layer or layers of vacuum deposited material, asillustrated by the geometric physiologically functional features 116 inFIG. 7E, recesses disposed through one or more layers of vacuumdeposited material, as illustrated by the recesses 122 in FIG. 8B or therecesses 136 or 138 in FIG. 9B, has an inherently different structurethan a block of material having recesses cut into it. The reason forthis inherent difference lies in the differences in the materials makingup surfaces exposed by the recesses. For example, in the case of a blockof material and assuming that the block material is uniform in regard tomaterial properties, an undisturbed surface of the block and a surfacewithin a recess or groove cut into the block have the same materialproperties.

In contrast, layers of different vacuum deposited materials can bedeposited to create recessed and/or elevated surfaces having inherentlydifferent material properties. In fact, layers of the same vacuumdeposited material can be deposited having differences in grain size,grain phase, and/or surface topography. The alternative grain size,grain phase, and/or surface topography may be included or formed, by wayof example, any of the methods disclosed in commonly assigned U.S.patent application Ser. No. 12/428,981, filed Apr. 23, 2009,incorporated by reference herein. For example, surfaces of the recesses122, 136 can be deposited to have a roughened surface topography and alarge grain size and surfaces of the material deposited defining therecesses 122, 136, for example the layer 120 illustrated in FIG. 8B, canhave a relatively smoother surface topography and/or a smaller grainsize.

In addition to utilization of the above described geometricphysiologically functional features, endothelial migration may befurther promoted by geometrically tailored leading and trailing edgesurfaces of structural members of the implantable device and/or by theaddition of surface structural features thereto. For example, referringto FIG. 10, an artery 200 is illustrated having an arterial wall 202. Animplantable medical device, for example, a stent 204 is illustratedbeing disposed within the artery 200 in engagement with the arterialwall 202. The stent 204 may include a plurality of structural members206 that are interconnected. As evident from the cross-sectional viewillustrated in FIG. 10, correct placement of the structural members 206relative to the arterial wall 202 results in a plurality of tissuemounds 208 protruding between the structural members 206.

FIG. 10 further illustrates an exemplary direction 210 of blood flow,which is generally parallel to a longitudinal axis 212 of the artery200. Endothelial regeneration of the arterial wall 202 proceeds in amulticentric fashion following implantation of the structural members206. However, due to stresses associated with the direction 210 of bloodflow, the endothelial regeneration may include a preferred direction ofmigration. Further, individual structural members 206 may have distinctsurface regions experiencing different types of stress depending onorientation of the individual structural members 206 relative to thedirection 210 of blood flow.

Referring to FIGS. 10 and 11, as well as FIGS. 21A-B and FIGS. 22A-B thestructural member 206 (circled in FIG. 10) includes a leading edge 214relative to the direction of blood flow 210 and a trailing edge 216relative to the direction of blood flow 210. The leading edge 214 is thefirst edge to experience or interact with the blood flow 210, while thetrailing edge 216 subsequently interacts with the blood flow 210 afterthe blood flow 210 leaves the leading edge 214. Referring to FIG. 11,the structural member 206 may have a surface region 218 on the leadingedge 214 that experiences shear stress due to the direction 210 of bloodflow. Shear stress in fluids is the parallel or tangential force appliedover the cross section of an area. This shear stress is dependent on thevelocity of blood flow. The velocity of blood flow may range betweenabout 0.05 to 0.2 m/s depending on the location of the stent, bloodpressure, blood vessel flexibility, and the like.

The leading edge 214 of the structural member 206 may have a pluralityof surface regions 218, 222 that are exposed to shear and/or normalstress associated with the direction 210 of the blood flow. For example,referring to FIG. 10, shear stress at surface region 218 is provided bya component 220 of blood flow along the leading edge 214. Increasing theangle measured between the leading edge 214 of the surface region 218and the direction 210 of blood flow decreases the magnitude of thecomponent 220 of blood flow, and therefore reduces the shear stress atthe surface region 218. A leading edge that is oriented generally normalto blood flow may experience stress that is substantially normal havinglittle or no shear component. For example, at surface region 222illustrated in FIG. 10, the component 220 and component 224 of bloodflow may cancel out leaving only a generally normal stress associatedwith the direction 210 of blood flow directed along the longitudinalaxis 212.

Similarly, the trailing edge 216 of the structural member 206 may have aplurality of surface regions 226 that are exposed to shear and/or normalstress associated with the direction 210 of the blood flow. For example,referring to FIGS. 10, 21A and 22A shear stress at surface region 226 isprovided by a component 228 of blood flow along the trailing edge 216.Increasing the angle measured between the trailing edge 216 of thesurface region 226 and the direction 210 of blood flow decreases themagnitude of the component 228 of blood flow, and therefore reduces theshear stress at the surface region 226. A trailing edge that is orientedgenerally normal to blood flow (See FIG. 13A) may be in a low flow eddyregion and may experience little or no stress associated with thedirection 210 of blood flow directed along the longitudinal axis 212.

Referring to FIG. 12A, the leading edge 214 of the structural member 206includes a generally rounded rectangular cross-section is illustratedoriented substantially normal to the direction 210 of blood flow.Referring to FIG. 12B, the leading edge 214 of the structural member 206includes a generally hexagonal cross-section is illustrated orientedsubstantially normal to the direction 210 of blood flow. Referring toboth FIGS. 12A and 12B and not being bound by theory, blood flows aroundthe tissue mound 208 before reaching the leading edge 214, asillustrated by arrow 230. Proximate to the leading edge 214, blood isdiverted around the structural member 206 as indicated by arrow 232 andflows over a upstream surface region 242, then a second surface region234 of the leading edge 214, thereby causing a shear stress at thesecond surface region 234. The upstream surface region 242 is adjacentto the tissue mound 208, while the second surface region 234 isapproximately at an angle between 0 and 180 degrees. Blood continues toflow over a third surface region 236 (which is contiguous with thesurface 234) of the structural member 206, as illustrated by arrow 238,thereby causing a shear stress at the third surface region 236.

Note that a structural member having a generally rounded rectangularcross-section may result in formation of an eddy region as indicated bycurved arrow 240 in FIG. 12A. The eddy region 240 represents a region oflow flow and may be associated only weakly with normal and/or shearstress at the upstream surface region 242. Thus, in this geometry, ECmigration over the upstream surface region 242 would not benefit fromexposure to shear stress as would EC migration over the second and thirdsurface regions 234, 236. Not wishing to be bound by theory, it iscontemplated that EC migration from a source of EC to a surface region,such as from the tissue mound 208 to the third surface region 236, wouldbe enhanced by a continuous shear stress applied from the tissue mound208 to the third surface region 236. Such continuous shear stress is notevident in the geometry illustrated in FIG. 12A.

Referring now to FIG. 12B, the eddy region as indicated by curved arrow240 may also be formed with this cross-sectional geometry; however, inthis geometry the eddy region 240 is associated with a smaller upstreamsurface region 242 compared with the eddy region 240 illustrated in FIG.12A. Thus, although the hexagonal cross-sectional geometry for thestructural member 206 may be an improvement over the generally roundedrectangular cross-section illustrated in FIG. 12A, the upstream surfaceregion 242 would not be exposed to shear stress. Thus, continuous shearstress from the tissue mound 208 to the third surface region 236 is notevident in the geometry illustrated in FIG. 12B.

Referring to FIGS. 12C-12D and 21A-21B, the leading edge 214 of thestructural member 206 includes a modified cross-section is illustratedoriented substantially normal to the direction 210 of blood flow. Afirst edge 211 forms a first surface region 213. The first edge 211joins the leading edge 214 adjacent to the tissue mound 208 to form thesecond surface region 234 including generally J-shaped cross-section oran elliptical, concave curvilinear, or circular cross-section to couplethe blood flow from the tissue mound 208 and create shear stress at thesecond surface region 234. In this cross-sectional geometry, not wishingto be bound by theory, the blood flows around the tissue mound 208before reaching the leading edge 214, as illustrated by arrow 230.Proximate to the leading edge 214, the blood flow is diverted around thestructural member 206, as indicated by arrow 232, and flows over asecond surface region 234 of the leading edge 214, thereby causing shearstress at the second surface region 234. Blood continues to flow overthe third surface region 236 (which is contiguous with the surface 234)of the structural member 206, as illustrated by arrow 238, therebycausing a shear stress at the third surface region 236. Preferably,increased shear stress is about 15 dynes/cm2 caused by the blood flowfrom the second surface region to the third surface regions, wherebyEC's will migrate roughly at a rate of 25 μm/hr or about 2.5 times thediameter of an EC, which is nominally 10 μm. Further such migration hasbeen observed in the direction of the blood flow with little migrationobserved against the flow. Alternatively, the configuration of thesecond surface region 234 generates shear stress increased from normalblood flow, which is a pressure of about 1.5 dynes/cm2. As such, theconfiguration is optimized to increase the shear stress of the bloodflow to be a pressure between about 5 and 25 dynes/cm2 at the thirdsurface region 236.

Note that blood flow over the leading edge 214 of the structural member206 having the modified cross-sectional geometry illustrated in FIG. 12Centirely lacks an eddy region. The structural member thus retains ageneral cross section in a generally, hexagonal, trapezoidal, polygonal,or an arrow-head configuration. In this geometry, blood flows over thetissue mound 208 and over the second surface region 234, which iscontiguous between the tissue mound 208 and the third surface region236. Such blood flow provides shear stress to the tissue mound 208 andthe second surface region 234 contiguously. Thus, in this geometry, ECmigration benefits from continuous exposure to shear stress from thetissue mound 208 to the third surface region 236. In one embodiment, thetrailing edge 216 is symmetrical with the leading edge 214 and includesa modified cross-section is illustrated oriented substantially normal tothe direction 210 of blood flow to include a generally J-shapedcross-section or an elliptical, concave curvilinear, or circularcross-section to couple the blood flow. The trailing edge 216 mayinclude a radius curvature similar to that of the leading edge 214 andthe second surface region 234. Preferably, the trailing edge 216includes a surface region as to enforce the shear stress on the thirdsurface region and maintain the shear stress on the trailing edge's 216surface region. Alternatively, the trailing edge 216 may beasymmetrical.

As shown in FIG. 12D, the second surface region 234 includes a radius ofcurvature Rs. Preferably, the radius of curvature Rs is the reciprocalof a radius approximately 1/Rs, where Rs is between about 1 μm to about75 mm, alternatively from about 1 nm to about 50 mm, alternatively fromabout 1 nm to about 2000 μm, and preferably from about 1 nm to about 200mm. The radius curvature Rs of the second surface region 234 may beselected for the particular tissue mound 208 that might be adjacent tothe structural member 206. For example, the radius of curvature Rs maybe selected to be greater where the tissue mound 208 is found to grow ata height Ht greater than the height, thickness or width of thestructural member 206. Such a tissue mound 208 with a height Ht greaterthe height or thickness of the structure member 206 would require agreater degree of curvature to retain a contiguous blood flow from thetissue mound 208 over the second surface region 234 and to the thirdsurface region 236, as to provide shear stress to the tissue mound 208for continual EC migration over such regions. Preferably, the height ofthe second surface region 234 is above the height of the connectingpoints of the leading edge 214 and the first edge 211 and above theheight of the connecting points of the trailing edge 216 and the thirdedge 216. The differential in the height of the second surface region234 may also provide for the continuous shear stress from the secondsurface region 234 to the third surface region 236.

As shown in FIG. 12D, the leading edge 214 of the second surface region234 combines with the first edge 211 to form an angle As. Preferably,angle As is less than 90 degrees, alternatively, between about 1 and 80degrees, alternatively, between about 10 and 75 degrees, alternatively,between about 20 and 60 degrees. The angle As is generally acute, suchas to provide the tissue mound 208 to grow into the first edge 211 onabout a generally angular or sloped configuration. The second surfaceregion 234 connects to the third surface region 236 to form an angle At.Preferably, angle At is greater than 90 degrees, alternatively, betweenabout 90 and 179 degrees, alternatively, between about 100 and 160degrees, alternatively, between about 120 and 140 degrees. The angle Atis generally obtuse, such as to provide the contiguous shear stress 238from the surface 234 of the structural member 206 to the third surfaceregion 236. In one embodiment, the length Lt of the third surface region236 is less than the length Ls of the second surface region 234, as tomaintain the contiguous shear stress over the third surface region 236.Length Ls and length Lt may be between about 1 μm to about 75 mm,alternatively from about 1 nm to about 50 mm, alternatively from about 1nm to about 2000 μm, and preferably from about 1 nm to about 200 mm.Preferably, the strut thickness is below 250 μm for properendothelialization.

In one embodiment, the first edge 211 joins the second edge 215; wherebythe second edge 215 joins a third edge 217, as shown in FIGS. 12C-12D.The third edge 217 joins the trailing edge 216 to form the substantiallyhexagonal cross-sectional configuration. In this embodiment, the secondedge forms a sixth surface 219, and the third edge 217 forms a fifthsurface 221. While a hexagonal configuration is shown, alternativepolygonal configuration may be utilized that maintain the geometry forblood flows over the tissue mound 208 and over the second surface region234 to be contiguous between the tissue mound 208 and the third surfaceregion 236 and to provide for shear stress to the tissue mound 208 andthe second surface region 234 contiguously. In one embodiment, the firstedge 211 joins the second edge 215 at a generally obtuse angle,preferably, greater than 90 degrees, alternatively, between about 90 and179 degrees, alternatively, between about 100 and 160 degrees,alternatively, between about 120 and 140 degrees. In one embodiment, thesecond edge 215 joins the third edge 217 at a generally obtuse angle,preferably, greater than 90 degrees, alternatively, between about 90 and179 degrees, alternatively, between about 100 and 160 degrees,alternatively, between about 120 and 140 degrees.

Referring to FIG. 13A, the trailing edge 216 of the structural member206 including a generally rounded rectangular cross-section isillustrated in one embodiment oriented substantially normal to thedirection 210 of blood flow. Not wishing to be bound by theory, theblood flows 340 over a third surface region 236 of the structural member206, as illustrated by arrow 338, thereby causing a shear stress at thesurface region 236. In one embodiment, the surface region issubstantially perpendicular to the longitudinal axis of the structuralmember 206. The blood flows 340 over the trailing edge 216 and continuespast the tissue mound 208, as illustrated by arrow 340. An eddy region,as represented by arrow 342, is formed in the wake of the structuralmember 206 between the tissue mound 208. The eddy region 342 representsa region of low flow and may be associated only weakly with normaland/or shear stress at a downstream surface region 344 bound by thestructural member and vessel, which is substantially perpendicular tothe surface region 236. Thus, in this geometry, EC migration over thedownstream surface region 344 would not benefit from exposure to shearstress as would EC migration over the third surface region 236. Notwishing to be bound by theory, the EC migration over a surface region,such as the distal surface region 344, would be enhanced by shear stressresulting from the flow of blood thereover. Such shear stress is notevident for the surface region 344 in the geometry illustrated in FIG.13A.

Referring to FIG. 13B, one embodiment of the trailing edge 216 of thestructural member 206 having a modified cross-section is illustratedoriented substantially normal to the direction 210 of blood flow 340.Not wishing to be bound by theory, blood flows over the third surfaceregion 236 of the structural member 206, as illustrated by the arrow338, thereby causing a shear stress at the third surface region 236. Thethird surface region 236 is substantially perpendicular to thelongitudinal axis of the structural member 206. Blood flows over thetrailing edge 216 and continues past the tissue mound 208, asillustrated by arrow 340. In this embodiment, the trailing edge 216includes a curvilinear or elliptical cross-section to form a fourthsurface region 346, which is curvilinear or elliptical relative to thetissue mound 208. Note that blood flow 340 over the trailing edge 216 ofthe structural member 206 having the modified cross-sectional geometryillustrated in FIG. 13B and entirely lacks an eddy region. Thus, in thisgeometry, the blood flows over the fourth surface region 346 of thetrailing edge 216. EC migration over the fourth surface region 346thereby benefits from exposure to shear stress as would EC migrationover the surface region 236. Not wishing to be bound by theory, the ECmigration over the fourth surface region 346 would be enhanced by shearstress resulting from the flow of blood 340 thereover.

As shown in FIG. 13C, the fourth surface region 346 includes a radius ofcurvature Rr. Preferably, the radius of curvature Rr is the reciprocalof a radius approximately 1/Rr, where Rr is between about 1 nm to about75 μm, from about 1 μm to about 75 mm, alternatively from about 1 nm toabout 50 mm, alternatively from about 1 nm to about 2000 μm, andpreferably from about 1 nm to about 200 mm. Preferably, the radius ofcurvature maintains the thickness of the structural member below 250 μmas to maintain endothelialization. The radius curvature Rr of the fourthsurface region 346 may be selected for the particular tissue mound 208that might be adjacent to the structural member 206. For example, theradius of curvature Rr may be selected to be greater where the tissuemound 208 is found to grow at a height Ht greater than the height,thickness or width of the structural member 206. Such a tissue mound 208with a height Ht greater the height or thickness of the structure member206 would require a greater degree of curvature to retain a contiguousblood flow from the tissue mound 208 over the third surface region 236and to the fourth surface region 346, as to provide shear stress to thetissue mound for continual EC migration over such regions. Preferably,the height of the second surface region 236 is above the height of theconnecting points of the leading edge 214 and the first edge 211 andabove the height of the connecting points of the trailing edge 216 andthe third edge 217. The differential in the height of the second surfaceregion 234 may also provide for the continuous shear stress from thesecond surface region 234 to the fourth surface region 346.

As shown in FIG. 13C, the trailing edge 216 of the fourth surface region346 combines with the third edge 217 to form an angle Ar. Preferably,angle Ar is less than 90 degrees, alternatively, between about 1 and 80degrees, alternatively, between about 10 and 75 degrees, alternatively,between about 20 and 60 degrees. The angle Ar is generally acute, suchas to provide the tissue mound 208 to grow into the third edge 217 onabout a generally angular or sloped configuration. The third surfaceregion 336 236 connects to the fourth surface region 346 to form anangle Aq. Preferably, angle Aq is greater than 90 degrees,alternatively, between about 90 and 179 degrees, alternatively, betweenabout 100 and 160 degrees, alternatively, between about 120 and 140degrees. The angle Aq is generally obtuse, such as to provide thecontiguous shear stress 340 from the surface 336 236 of the structuralmember 206 to the fourth surface region 346. In one embodiment, thelength Lt of the third surface region 336 236 is less than the length Lrof the fourth surface region 346, as to maintain the contiguous shearstress over the fourth surface region 346, as shown in FIG. 13B.

In one embodiment, the third edge 217 joins the second edge 215, wherebythe second edge 215 joins the first edge 211, as shown in FIGS. 13B-13C.The first edge 211 joins the leading edge 214 to form the substantiallyhexagonal cross-sectional configuration. While a hexagonal configurationis shown, alternative polygonal configurations may be utilized thatmaintain the geometry for blood flows over the third surface region 336236 and be contiguous between the fourth surface region 346 and thetissue mound 208 and to provide for shear stress to the tissue mound 208and the second surface region 234 contiguously

Instead of or in addition to geometrically tailored leading and trailingedge surfaces of the structural members 206, as described hereinabovewith regard to FIGS. 12A-13C, endothelial migration across animplantable device may be promoted by the addition grooves to surfacesof the implantable device. When a groove is disposed, or provided, on,or in, a surface of an intravascular stent, the rate of migration ofendothelial cells upon the surface may be increased over that rate ofmigration which would be obtained if the surface were not provided withthe groove. Further, EC within a groove oriented with blood flowexperience shear stress of the blood flow directly and would thereforebe expected to migrate in the direction of the blood flow as describedhereinabove. The formation of the grooves may be achieved by the methodsin commonly assigned U.S. patent application Ser. No. 09/861,219, filedMay 10, 2001 and Ser. No. 13/099,980, filed May 3, 2011, bothincorporated by reference herein.

Referring to FIG. 14A, the structural member 207 includes a luminalsurface 436 as well as a leading edge 414 and a trailing edge 416relative to the direction 210 of blood flow. Referring to FIG. 14B, anyor all of the luminal surface 436, the leading edge 414, and thetrailing edge 416 may include grooves disposed therein or thereon. Forexample, in one embodiment, the luminal surface 436 may have grooves 418disposed therein. The grooves 418 may be oriented in any directionrelative to the direction 210 of blood flow; however, orientation of thegrooves 418 parallel to the direction 210 of blood flow, as illustratedin FIG. 14B, exposes EC within the grooves 418 to shear stress caused bythe blood flow. As noted hereinabove, such exposure of EC to shearstress increases the rate of migration of the EC.

The leading edge 414 of the structural member 406, in one embodiment,may include grooves 420 disposed therein or thereon. The grooves 420 maybe oriented in any direction relative to the direction 210 of bloodflow. In one embodiment as illustrated in FIG. 14B, the grooves 420 areoriented such that a component of blood flow along the leading edge 414(for example, see the components 220 and/or 224 in FIG. 10) exposes ECwithin the grooves 420 to shear stress caused by the blood flow.Similarly, the trailing edge 416 of the structural member 406, in oneembodiment, may include grooves 422 disposed therein or thereon. Thegrooves 422 may be oriented in any direction relative to the direction210 of blood flow. In one embodiment as illustrated in FIG. 14B, thegrooves 422 are oriented such that a component of blood flow along thetrailing edge 416 (for example, see the component 228 in FIG. 10)exposes EC within the grooves 422 to shear stress caused by the bloodflow.

It should be noted that the addition of the grooves 418, 420, 422 to oneor more of the surfaces 436, 414, 416, may be instead of or in additionto any embodiment of the geometric physiologically functional featuresas described hereinabove with regard to FIGS. 1-9B. For example, any orall of the grooves 418, 420, 422 illustrated in FIG. 14B may be disposedin a layer or layers of vacuum deposited material including ahomogeneous molecular pattern of distribution. Further, the grooves 418,420, 422 may be disposed through one or more layers of vacuum depositedmaterial, having differences in grain size, grain phase, and/or surfacetopography.

Any of the geometrically functional features or recesses may also beincluded in the trailing edge, leading edge, or surface regions toenhance the endothelial migration and attachment to such surfaces.

An implantable device may include problematic surfaces that may beresistant to endothelialization or may otherwise be relatively slow toendothelialize. The problematic surfaces may be disadvantaged for celladhesion because of, for example, hemodynamic reasons such as disruptionvia turbulence or low shear stress (which may occur in thick stents, forexample, greater than about 100 μm) or chemical reasons such asanti-mitotic and/or anti-inflammatory drugs. The problematic surfacescould be, for example, stent bridges disposed at various angles againstthe blood flow.

Referring to FIG. 15, it is contemplated that a combination of properlyoriented grooves may facilitate EC migration to the problematic surfacesand/or promote cell stability thereon. For example, in one embodiment, amain highway 500 of the grooves 418 may be disposed in the luminalsurface 436 of the structural member 406 and oriented generally parallelto the direction 210 of blood flow, as illustrated in FIG. 15. The mainhighway 500 could provide an abundance of migrating EC, which could bediverted therefrom to a problematic surface, for example, a surface 502on a transversely disposed structural member 506 of the implantabledevice.

It is further contemplated that diversion of migrating EC from the mainhighway 500 could be applied to surfaces having a specific function,which may or may not otherwise be conducive to EC migration. Forexample, referring to FIG. 15, the structural member 506 may includesurfaces including a plurality of pores 508 as might be found, forexample, in a drug eluting stent.

It is contemplated that a factor in increasing endothelialization of asurface of an implanted medical device may be the cleanliness of thesurface. In this context, cleanliness refers to the presence or lack ofcontaminant molecules bonding to otherwise unsaturated chemical bonds atthe surface. A perfectly clean surface, for example as may exist in avacuum, comprises unsaturated bonds at the surface. The unsaturatedbonds provide the surface with a higher surface energy as compared to acontaminated surface having fewer unsaturated bonds.

The method disclosed herein comprehends the creation of a patternedarray of geometric physiologically functional features elevated relativeto a surface of an implantable biocompatible material, recessed relativeto the surface, or disposed on the surface. For example, in accordancewith an alternative embodiment, the implantable biocompatible materialis formed of a bulk material of titanium, nickel-titanium alloy or othertitanium-rich alloy metals or a top most layer of titanium,nickel-titanium alloy or other titanium-rich alloy metals deposited overthe bulk material. The titanium, nickel-titanium alloy or othertitanium-rich alloy metal is oxidized to convert surface titanium totitanium dioxide, then covered with a pattern-mask and exposed to highintensity UV irradiation. It is well-known that titanium dioxide (TiO₂)absorbs UV radiation and has been used in a variety of applications as aUV inhibitor to prevent UV transmission across a TiO₂ barrier layer. Ithas been discovered that upon exposure to UV irradiation, an originallyhydrophobic and oleophilic titanium oxide layer becomes amphiphilic.

The effect of UV irradiation on a titanium oxide surface is believed tooccur because of unsymmetrical cleavage of the Ti—O bond to leave Ti³⁺ions on the surface in some regions. Presently, these amphiphilicsurfaces are being used in a range of technological applications, suchas self-cleaning paints and anti-misting glasses. It has been recognizedthat these amphiphilic titanium oxide layers have use in medicalapplications. Zarbakhsh, A., Characterization of photon-controlledtitanium oxide surfaces, ISIS Experimental Report, Rutherford AppeltonLaboratory, May 16, 2000 (which may be found on the internet at:www.isis.r1.ac.uk/isis2001/reports/11144.pdf).

The amphiphilic state of the UV irradiated titanium oxide may beemployed as an alternative to depositing patterned elevated or recessedgeometric physiologically functional features onto the implantablebiocompatible material. An implantable biocompatible material fabricatedhaving a bulk substrate or a top most vacuum deposited layer of titaniumor a titanium alloy is masked with a pattern mask having a plurality ofopenings passing there through. As with the above-described embodiment,the plurality of openings preferably have a size and special arrayselected to define affinity binding domains and cellular migration citesfor promoting endothelial cell binding and proliferation across thesubstrate surface.

The open surface area of each of the plurality of openings in thepattern mask is preferably in the range of between about 1 nm to about75 μm, and with adjacent pairs of openings being in a spaced apartrelationship such that a distance of about 1 nm to about 75 μm existsbetween the openings, the inter-opening being greater than, about equalto, or less than the size of the opening. By interposing the patternmask between a UV source and the surface of the implantablebiocompatible material, a pattern of UV irradiated regions is impartedto the surface implantable biocompatible material, thereby altering thetitanium dioxides present at the irradiated regions and forming affinitydomains at the surface implantable biocompatible material.

Referring to FIG. 6A, a portion of an implantable material 56 made oftitanium or a titanium-alloy is shown having at least one surface 52 and54 that is oxidized by heating or an equivalent known by the personskilled in the art.

Referring to FIG. 6B, a machined mask 48 that had laser-cut holes 40 ofdefined size from about 1 nm to about 75 μm, from about 1 nm to about 50μm, from about 1 nm to about 2000 nm, and preferably from about 1 nm toabout 200 nm, patterned throughout to coat the at least one surface 52of the implantable material 56 and is tightly adhered to the coveredsurface 52.

Referring to FIG. 6C, the implantable material 56 covered with the mask48 is then illuminated by the ultraviolet rays. Because TiO₂ issensitive to ultraviolet, the chemical composition of the portions 58 ofthe surface 52 in the holes is different from the area that is coveredby the mask.

Referring to FIG. 6D, after ultraviolet irradiation, the mask is removedto reveal the surface 52 that surrounds the geometric physiologicallyfunctional features 59 formed by ultraviolet irradiation. As describedabove, because the shape of the holes 40 in the mask 48 could be in anyof the shapes described for the geometric physiologically functionalfeatures including: circle, square, rectangle, triangle, parallel linesand intersecting lines, and combinations thereof, the geometricphysiologically functional features 59 accordingly adopts such shapesalso. In contrast to the geometric physiologically functional featuresillustrated in FIGS. 5C, 7E, 8B, and 9B, the geometric physiologicallyfunctional features 59 in FIG. 6C are not elevated and therefore havezero thickness relative to the surrounding surface of the implantablematerial.

Example 1

Nickel-titanium sheets were heated to oxidize titanium present at thesurface of the sheet. Pattern masks fabricated from machined metal werelaser drilled a pattern of holes having diameters ranging from 15 μm to50 μm, with a single diameter of holes on each pattern mask. A singlepattern mask was placed over a single nickel-titanium sheet and theassembly was exposed to high intensity ultra-violet irradiation. AfterUV irradiation, the irradiated nickel-titanium sheet was placed on afully endothelialized test surface and maintained at 37° C. undersimulated in vivo flow conditions and under static flow conditions.Qualitative observations were periodically made and it was found thatendothelial cells bound to the pattern of UV irradiated affinity domainsand migrated across the nickel-titanium sheet by proliferating acrossthe pattern of affinity domains, eventually fully seeding endothelium onthe nickel-titanium sheet.

Example 2

Human aortic EC migration onto 1×1-cm, 316L stainless steel flat couponsafter fixation and Giemsa staining ECs were seeded and grown toconfluence on ammonium cross-linked, firm collagen gel, coveringrectangular polyester film sheet. Thin (600 μm) coupons then wereimplanted into endothelialized surface, such that top surface was flushwith gel surface. Entire sheet then was placed into parallel plate flowchamber and exposed to fluid-imposed arterial level shear (15dynes/cm²), as shown in FIG. 16A, and low shear (1.5 dynes/cm²), asshown in FIG. 16B, wall stress on right for 4 days. FIGS. 16A-16Bincludes an arrow indicates that direction of flow. With high shear, allcell migration occurs in direction of flow. At low shear, migration isdiminished and in all directions.

In static culture conditions, the rate of EC migration on a metalsurface such as stainless steel or nitinol is initially 10 μm/h andincreases to 15 μ/h 10 days later. In the presence of flow at normalshear rates, the migration rate increases to 25 m/h by 7 days. Withnormal shear, ECs migrate in the direction of flow with little migrationobserved against flow. With low shear, migration is slower and tends tooccur in every direction, as shown in FIGS. 16A-16B. This observationagrees with the fact that coronary stents placed with minimal injury tothe endothelium may require only a few days to endothelialize. Incontrast, in stents placed in totally occluded vessels or after largeendothelial injury, such as after catheter endarterectomy or laserrevascularization, endothelializaton time may be prolonged from severalweeks to a few months.

In addition to flow shear, the topography of the surface plays a role inEC coverage. An obstacle raised above the plane of the vessel's innersurface, such as an intravascular stent, hinders cell progression in amanner proportional to its height. Because stents have complexgeometries, an experimental model of a stent was made with simple shapesof flat material with a thickness commensurate with the thickness ofvascular stents. Pieces of progressively increasing heights from 25 to250 μm were placed on a monolayer of ECs in a laminar flow chamber atphysiologic wall shear stress (15 dynes/cm²). The number of cells ableto gain access on top of the obstacles decreased significantly withheights of 100 μm and greater as compared with 25 μm. No cells werefound on top of 250 μm-thick obstacles, as shown in FIG. 17. Theseexperimental results agree with clinical experience with intravascularstents having increased failure rates with increasing wall thickness.Two coronary stents of identical design and wall thicknesses of 50 and140 μm encountered significantly higher clinical and angiographicrestenosis rates with the later. This reflects impairedendothelialization and increased intimal formation with the largerobstacles caused by thicker stent struts.

With slow motion video recordings of ECs migrating on a flat surfaceunder flow, cells migrate downstream not in straight lines but rather ina zigzag pattern. This motion increases the probability of encounterwith other migrating cells. Cell collisions reduce migration speed bycontact inhibition. Multiple collisions halt migration and allowconfluence. If a migrating cell encounters a linear feature on thesurface, such as a scratch disposed at an angle to the direction offlow, it follows the feature, as shown in FIG. 18. If multiple parallelscratches are made on the surface, the cells migrate in straight linesalong the scratches, as shown in FIG. 19. The migration speed is thusincreased because the side to side movement is inhibited. The increasein migration speed reflected on the cell count on the leading edge ofthe material is dependent on the width of the grooves, as it relates tocell size, as shown in FIG. 20. Narrow grooves prevent cell progression,and excessively large grooves allow the cells to wander, thereforeslowing down migration speed. With stents with microscopic parallelgrooves created on the inner surface, significantly acceleratedendothelialization rates were found in carotid artery stents of pigs 1week after placement. With the hypothetic assumption that no endothelialdamage is produced by the stent placement, ECs adjacent to the raisedstent struts slough because of superficial microflow disturbances. Thisis shown experimentally by measuring the area devoid of ECs shortlyafter placement of geometric obstacles on an EC monolayer. The angle ofthe sides of the object relative to the flow direction influences theextent of endothelial slough. The lowest EC loss is observed adjacent tothe edges along the flow, and the largest on the down flow side of edgesdisposed transversely. Intermediate degrees of EC loss were found on thetransverse upstream edge and on the 45-degree edge. This findingsupports the clinical experience of higher restenosis rates for coiledstents with struts substantially perpendicular to the direction of flow.

The influence of the edge angle of stent struts in the vertical axis(radial direction in a vessel lumen) also was evaluated. Shallow anglesin objects disposed perpendicular to flow allowed the largest number ofcells to migrate on top of the obstacle. This observation indicates thatstent struts should have blunted edges or, even better, a trapezoidalcross section as indicated above.

The density of the stent mesh has an influence on the intimalhyperplastic response. Stents with few struts spaced far apart producemore intimal hyperplasia than more struts around the circumference ifthey are evenly distributed. This is related to wall indentation with afew stent struts producing a polygonal rather than a circumferentiallumen. However, increased strut density may come at the price of largermetal surface, and this in turn may affect patency. Of course, the manyvariables influenced by stent design, such as total metal surface,radiopacity, radial strength, expandability ratio, shortening, andflexibility, affect each other. Typically, compromises must be reachedto attain the best possible results within technical limitations.

While the present invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art willunderstand and appreciate that variations in materials, dimensions,geometries, and fabrication methods may be or become known in the art,yet still remain within the scope of the present invention which islimited only by the claims appended hereto. It is understood, therefore,that this disclosure is not limited to the particular embodimentsdisclosed, but it is intended to cover modifications that may include acombination of features illustrated in one or more embodiments withfeatures illustrated in any other embodiments. Various modifications,equivalent processes, as well as numerous structures to which thepresent disclosure may be applicable will be readily apparent to thoseof skill in the art to which the present disclosure is directed uponreview of the present specification. Accordingly, this description is tobe construed as illustrative only and is presented for the purpose ofenabling those skilled in the art to make and use the implantablemedical device having enhanced endothelial migration features describedherein and to teach the best mode of carrying out the same.

I claim:
 1. A tubular implantable medical device having enhancedendothelial migration features, comprising: a plurality of structuralmembers, each of the plurality of structural members having an irregularpolygonal transverse cross-sectional profile, wherein each facet of theirregular polygonal transverse cross-sectional profile defines a surfaceof the plurality of structural members, wherein the defined surfaces ofthe plurality of structural members make up abluminal surfaces engagedwith a vessel and luminal surfaces exposed to a blood flow, wherein theluminal surfaces form a transverse cross-sectional profile comprising aconcave curvilinear second surface region and a concave curvilinearfourth surface region, the second surface region and the fourth surfaceregion being interconnected by an intermediate generally planar thirdsurface region; wherein at least the third surface region comprises atleast one groove disposed within the third surface region, the groovegenerally parallel to the direction of blood flow.
 2. The tubularimplantable medical device of claim 1, wherein the shear stressgenerated at the second surface region is between about 5 and 25dynes/cm2.
 3. The tubular implantable medical device of claim 1, whereinthe second surface region includes a radius curvature Rs, wherein Rs isbetween about 1 nm to about 75 mm.
 4. The tubular implantable medicaldevice of claim 3, wherein the second surface region joins an abluminalsurface to form an angle As, wherein the angle As is less than 90degrees, wherein at least one surface includes a plurality of pores. 5.The tubular implantable medical device of claim 4, wherein secondsurface region joins the third surface region to an angle At, whereinthe angle At is greater than 90 degrees.
 6. The tubular implantablemedical device of claim 5, wherein a length of the third surface regionis less than a length of the second surface region.
 7. The tubularimplantable medical device of claim 6, wherein the abluminal surfacesfurther comprise a first abluminal surface joining a second abluminalsurface and the second abluminal surface joining a third abluminalsurface, whereby the third abluminal surface joins the fourth surfaceregion to form a substantially hexagonal cross-section configuration ofthe structural member.
 8. The tubular implantable medical device ofclaim 7, wherein the fourth surface region includes a radius curvatureRs, wherein Rs is between about 1 nm to about 75 mm.
 9. The tubularimplantable medical device of claim 8, wherein the fourth surface regionjoins the third abluminal surface to form an angle Ar, wherein the angleAr is less than 90 degrees.
 10. The tubular implantable medical deviceof claim 9, wherein fourth surface region joins the third surface regionto an angle As, wherein the angle As is greater than 90 degrees.
 11. Thetubular implantable medical device of claim 10, wherein the length ofthe third surface region is less than a length of the fourth surfaceregion.
 12. The tubular implantable medical device of claim 11, whereinthe second surface region and the fourth surface region include aplurality of geometric physiologically functional features including afocal adhesion point for affinity binding of endothelial cells.
 13. Theimplantable medical device of claim 11, wherein the at least one grooveis between 7 to 20 μm wide.
 14. A method of forming a tubularimplantable medical device having enhanced endothelial migrationfeatures, comprising: forming a tubular structure comprising ofstructural members, the tubular structure having a central longitudinalaxis; forming the structural members to include a transversecross-sectional profile comprising a first surface region joined to aconcave curvilinear second surface region, the second surface regionjoined to a generally planar third surface region, the third surfaceregion joined to a concave curvilinear fourth surface region, the fourthsurface region joined to a fifth surface region, the fifth surfaceregion joined to a sixth surface region; and whereby the tubularimplantable medical device includes at least one groove disposed acrossat least one of the second surface region, the third surface region, andthe fourth surface region, the at least one groove being orientedgenerally parallel to the central longitudinal axis of the tubularstructure.
 15. The method of claim 14, further comprising forming thesecond surface region to include includes a radius curvature Rs, whereinRs is between about 1 nm to about 75 mm.
 16. The method of claim 15,further comprising joining the second surface region to the firstsurface region to form an angle As, wherein the angle As is less than 90degrees, wherein at least one surface including a plurality of pores.17. The method of claim 16, further comprising joining the secondsurface region to the third surface region at an angle At, wherein theangle At is greater than 90 degrees.
 18. The method of claim 17, furthercomprising joining the first surface region to the second surfaceregion, the second surface region to the third surface region, the thirdsurface region to the fourth surface region, the fourth surface regionto the fifth surface region, the fifth surface region to the sixthsurface region to form a substantially hexagonal cross-sectionconfiguration of the structural member.
 19. The method of claim 18,wherein the fourth surface region includes a radius curvature Rs,wherein Rs is between about 1 nm to about 75 mm.
 20. The method of claim19, further comprising joining the fourth surface region to the fifthsurface region to form an angle Ar, wherein the angle Ar is less than 90degrees.